Aspirin (O-acetylsalicylic acid) is well known for treatment of inflammation, fever and pain and is also well established for secondary stroke prevention (The SALT Collaborative Group, 1991, Lancet 338 1345-1349). In regard to the latter, aspirin is known to inhibit the synthesis of thromboxane A2 in platelets by irreversible acetylation of a serine residue close to the active site of cyclooxygenase, an enzyme which catalyses the formation of an unstable endoperoxide intermediate, PGH2, from arachidonic acid (Lecomte et al, 1994, J. Biochem. 269 13207-13215). Thromboxane A2 is a vasoconstrictor and platelet-aggregating agent and is thus potentially thrombotic.
Whilst such an anti-thromboxane A2 effect may be desirable, aspirin also has a destructive effect on the vascular endothelium since it can inhibit synthesis of prostacyclin by a similar mechanism. Prostacyclin, in this regard, is a vasodilator that inhibits platelet aggregation and is thus potentially anti-thrombotic. In the stomach, prostacyclin is one of the important endogenous prostaglandins that provide local cytoprotection, induce gastric mucosal vasodilation, inhibit acid secretion and conserve gastric mucosal integrity (Gaskill et al, 1982, Surgery 92 220-225; Ligumsky et al, 1982, Am. J. Physiol. 242 G337-341; Walus et al, 1980, Proc. Soc. Exp. Biol. Med. 163 228-232). Aspirin therefore has paradoxical effects, being both a beneficial antiplatelet drug and a significant ulcerogen.
It has been proposed that an optimal antithrombotic effect can be achieved by restricting aspirin to the portal circulation where selective inhibition of platelet cyclooxygenase can occur as distinct from the inhibition of vessel wall cyclooxygenase. In other words, this may have the effect of reducing thromboxane A2 production whilst preventing aspirin reaching the post-hepatic systemic circulation where it might also inhibit prostacyclin synthesis and concomitant promotion of thrombotic and/or ulcerogenic injury (Ali et al, 1980, Stroke 11 9-13; Siebert et al, 1983, Clin. Pharmacol. Ther. 33 367-374; Pedersen et al, 1984, N. Engl. J. Med. 311 1206-1211; Roberts et al, 1986, Lancet 1 1153-1154; McLeod et al, 1988, Austr. NZ. J. Med. 148 207).
Confining the inhibition of cyclooxygenase activity to the portal circulation depends on extensive first pass hepatic de-acetylation of the aspirin, forming platelet-inactive salicylate. Previous studies, however, have demonstrated that the extraction of aspirin by the liver is incomplete: hepatic availabilities being reported to be between 0.6 and 0.8 for man (Harris et al, 1969, J. Pharm. Sci. 58 71-75), sheep (Cossum et at, 1986, J. Pharm. Sci. 75 731-737) and rat (Iwamoto et al, 1982, J. Pharm. Pharmacol. 34 176-180; Wientjes et al, 1988, J. Pharmacol. Exp. Ther. 245 809-815). Thus, substantial quantities of aspirin bypass the liver through an inefficient hepatic extraction and aspirin is not restricted to the portal circulation.
Various aspirin analogues/derivatives have been described in the prior art with improved efficacy in relation to treatment of pain and inflammation. In U.S. Pat. No 5,599,959 (Hosmane et al), there is disclosed analogues of aspirin having the structure: wherein R is defined as being selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, I-propyl, n-butyl, I-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, phenyl, naphthyl and cyclohexyl. R1 is defined as being selected from the group consisting of hydrogen, a C1-C12 alkyl group, F, Cl, Br, I, CO2H, CONHR, CONR2, CO2R, CHO, COR, SO3R, SO2NHR, SO2NR2, OH, OR, OCOR, SH, SR, OCONHR, OCONR2, SCOR, SCONHR, SCONR2 and NH2, NHR, NHCOR and NR2. The foregoing aspirin analogues were shown by Hosmane et al to adsorb into membranes of red blood cell and to decrease membrane viscoelasticity of such cells. According to Hosmane et al, a decrease in membrane stiffness would lead to a decrease in flow resistance experienced by red cells, and hence, a decrease in their mean capillary transit times (mean cell transit time). A positive correlation was also shown to exist between the amount of membrane adsorption and the lipophilicity of the aspirin analogue. Accordingly, Hosmane et al teach that such aspirin analogues may be advantageously used to treat diseases which have origin in poor blood supply or circulation such as heart disease, stroke, painful leg, and calf muscles, chest pain, atherosclerosis and dry gangrene. Hosmane et al, however, neither teach nor suggest compounds having anti-platelet activity with enhanced hepatic clearance and low ulcerogenic potential.
Diflunisal (2′,4′-difluoro-4-hydroxy-3-biphenylcarboxylic acid) is a salicylic acid derivative and is known to be analogous to aspirin insofar as treatment of inflammation, fever and pain and propensity for gastrointestinal injury. Various diflunisal derivatives have been described in the prior art having enhanced analgesic potency and anti-pyretic activity compared to the parent drug. Related diflunisal compounds are disclosed in U.S. Pat. No 4,044,049 (Ruyle et al). This patent is directed broadly to substituted 5-(phenyl) benzoic acid esters having the general formula: wherein X(1-5), R, R1 and R3 are as defined hereinafter. The term R2 is defined in this specification as being selected from the group consisting of hydrogen, lower alkyl (such as methyl, ethyl, butyl pentyl, and the like), lower alkanoyl (where “lower” is referring to acetyl, propionyl, butyryl and the like having an upper limit of 4 carbon atoms), and lower alkenyl (such as allyl, butenyl, and the like). In this regard, it should be noted that the only lower alkanoyl ester of 5-(phenyl) benzoic acid exemplified in the specification is 2-acetoxy-5-(4′fluoropheny)-benzoic acid and no other. In particular, this patent is concerned with anti-inflammatory properties of these compounds. However, there is no explicit disclosure in Ruyle et al of O-medium and longer alkyl esters of diflunisal which are the subject of this application nor are there methods disclosed which can result in the production of such esters.
In light of the above, the prior art is deficient in the lack of effective compounds having anti-platelet activity, enhanced hepatic clearance and low ulcerogenic potential.
The current invention arises from the unexpected discovery that by increasing the carbon number in the ester O-acyl moiety of diflunisal and related compounds, a marked enhancement in hepatic extraction results with a simultaneous reduction in ulcerogenicity. This greater rate of hepatic elimination is considered to minimise exposure of these esters to the systemic circulation thereby minimising prostacyclin inhibition within the vessel endothelium. Surprisingly, it has also been found that these and other diflunisal esters have anti-platelet activity as well as hydroxyl radical scavenging properties which make them suitable for use as active agents for treatment and/or control of thrombosis and ischaemic/reperfusion injury of tissues such as liver.